Research Progress in the Off-Target Effects of Bacille Calmette–Guérin Vaccine
Introduction
The Bacille Calmette–Guérin (BCG) vaccine, a live attenuated bacterial vaccine derived from Mycobacterium bovis, is one of the earliest vaccines developed in the last century. It is the only licensed vaccine for the prevention of severe tuberculosis (TB) in children, although its protection diminishes with age. Currently, the BCG vaccine is one of the most widely administered vaccines globally, with 154 nations implementing policies to provide BCG vaccination to their populations as of 2020. Among these, 53 countries have achieved a population coverage rate of at least 95%.
Historically, Calmette first reported in the late 1920s that BCG vaccination reduced non-TB mortality in children by four-fold compared to unvaccinated children. Over the following decades, randomized controlled trials (RCTs) and observational studies across various countries provided accumulating evidence that BCG vaccination lessened non-TB neonatal mortality. A World Health Organization (WHO)-commissioned systematic review in 2013 reported a 30% reduction in all-cause mortality following neonatal BCG vaccination. Subsequent RCTs established that BCG vaccination reduced neonatal mortality by 38% and one-year mortality by 16%, with the majority of these reductions attributed to the decrease in TB-unrelated infections and disorders.
Off-Target Effects of BCG Vaccine
The off-target effects of the BCG vaccine refer to its protective benefits against infections and diseases unrelated to TB. These effects have been demonstrated across a wide range of conditions, including respiratory tract infections (RTIs), leprosy, malaria, viral infections, non-muscle-invasive bladder cancer (NMIBC), and autoimmune diseases.
On Infections
The reduction in infant mortality attributed to the BCG vaccine has prompted studies on its preventive benefits against RTIs, which are a leading cause of death in children under five years old. A community case-control study by Stensballe et al. found that BCG-vaccinated children had a lower risk of RTI caused by respiratory syncytial virus compared to unvaccinated children. A large-scale study involving children from 33 countries revealed a 17–37% reduction in the risk of suspected acute RTI. Additionally, a retrospective epidemiological study in Spain reported a 41.4% decrease in hospitalization rates for RTI among BCG-vaccinated children compared to unvaccinated children.
Evidence also suggests that the BCG vaccine may reduce RTI incidence among the elderly. An RCT in Indonesia demonstrated that monthly BCG vaccination for three months in older adults significantly reduced the prevalence of RTI compared to placebo. Similarly, an RCT in Greece found that elderly individuals who received a single dose of the BCG vaccine had a 79% lower risk of respiratory infections compared to placebo.
The BCG vaccine has also shown protective effects against other infections, such as leprosy and malaria. A meta-analysis of seven experimental investigations conducted between the 1960s and 2001 reported an overall protective effect of 26% against leprosy. Similarly, a cross-sectional study in South Africa involving 34,206 children under five years of age found a 6% reduction in malaria prevalence among BCG-vaccinated children.
On Viruses as Immunotherapy
Due to its off-target effects, the BCG vaccine has been explored as a non-specific immunotherapy for viral infections. For example, BCG vaccination has been used to treat cutaneous and genital warts caused by human papillomavirus (HPV). A placebo-controlled study with 50 participants revealed that 80% of patients achieved complete resolution of lesions after a six-week course of BCG treatment, compared to no response in the control group. Clinical trials in various countries have shown complete clearance rates of HPV-associated warts ranging from 37.0% to 65.0% following BCG vaccination.
BCG vaccination has also been found to reduce the frequency and duration of relapses of herpes simplex virus (HSV). A study showed that all patients with recurrent herpes simplex remained relapse-free for 4–6 months after a single dose of BCG, with 19.3% remaining relapse-free for three years and 9.2% for more than six years.
On Other Vaccines as Adjuvant
The BCG vaccine has been shown to enhance the immune response when administered in conjunction with other vaccines. For example, coadministration of the BCG vaccine and hepatitis B vaccine at birth significantly boosted cytokine induction and increased the antibody response to the hepatitis B vaccine. Clinical trials have also demonstrated that BCG vaccination at birth enhances antibody responses to other vaccines, including diphtheria, tetanus, pertussis, polio, haemophilus influenzae type b (Hib), and 13-valent pneumococcal conjugate vaccines.
On Non-Muscle-Invasive Bladder Cancer (NMIBC)
The BCG vaccine is widely recognized for its efficacy in treating NMIBC. A meta-analysis of 24 randomized clinical trials concluded that BCG maintenance therapy reduced the probability of tumor progression by 27% compared to control groups. Studies have also shown that BCG vaccine is superior to other chemotherapeutic agents, such as mitomycin C (MMC) and epirubicin, in reducing the recurrence rate, distant progression, and mortality of NMIBC.
On Autoimmune Diseases
The BCG vaccine has shown potential off-target effects on autoimmune diseases, including asthma, type 1 diabetes mellitus (T1DM), and multiple sclerosis (MS). For example, neonatal BCG vaccination has been associated with improved lung function in asthma patients. In T1DM, BCG vaccination has been shown to normalize glycosylated hemoglobin levels over an eight-year follow-up period. Additionally, BCG vaccination has been linked to a reduced risk of developing MS, with a 52% lower risk observed in patients who received the vaccine compared to placebo.
Mechanisms Explaining the Off-Target Effects of BCG Vaccine
Two primary mechanisms have been proposed to explain the off-target effects of the BCG vaccine: heterologous lymphocyte responses and trained immunity.
Heterologous Lymphocyte Responses
The BCG vaccine enhances immune responses to unrelated pathogens by activating CD4+ and CD8+ memory cells, which modulate Th1 and Th17 responses. This mechanism involves the production of cytokines such as interferon-gamma (IFN-g), interleukin-1 beta (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a), which play crucial roles in the immune response against infections.
In the context of NMIBC, the BCG vaccine activates natural killer (NK) cells, which recognize and eliminate bladder tumor cells. The therapeutic benefit of BCG is abolished when NK cells are depleted, highlighting their critical role in the anti-tumor response.
Trained Immunity
Trained immunity, also known as innate memory immunity, involves the long-term reprogramming of innate immune cells, such as monocytes and macrophages, through epigenetic and metabolic changes. BCG vaccination induces trained immunity by increasing the accessibility of transcription factors to DNA and promoting the activation of transcriptionally active histone modifications, such as trimethylation of lysine 4 at histone 3 (H3K4m3) and acetylation of lysine 27 at histone 3 (H3K27ac). These changes lead to the activation of genes encoding pro-inflammatory cytokines, such as IL-1b, TNF-a, and IL-6, which enhance the immune response against unrelated pathogens.
Factors Influencing Off-Target Effects of BCG Vaccine
Several factors influence the off-target effects of the BCG vaccine, including the vaccine strain, inoculation time, gender, and inoculation sequence.
BCG Vaccine Strains
Different BCG vaccine strains, such as the Bulgarian, Danish, Russian, and Japanese strains, have varying effects on immune responses. For example, the Danish strain has been shown to elicit a higher proportion of multifunctional cytokine responses compared to other strains.
Inoculation Time
The timing of BCG vaccination significantly impacts its off-target effects. Studies have shown that BCG vaccination at birth reduces all-cause mortality and unspecific infection rates compared to delayed vaccination.
Gender Disparity
The off-target effects of the BCG vaccine exhibit sex-specific differences. For example, boys show a lower mortality rate ratio (MRR) in the first week following BCG vaccination, while girls show a lower MRR at weeks 2–4.
Inoculation Sequence
The sequence of vaccination can also influence the off-target effects of the BCG vaccine. For example, BCG vaccination after or simultaneous with diphtheria-pertussis-tetanus (DTP) vaccine has been associated with a significantly decreased risk of acute lower RTI compared to DTP vaccination after BCG.
Discussion
The off-target effects of the BCG vaccine have significant implications for public health, particularly in regions with a high burden of infectious diseases. However, further research is needed to confirm these effects and elucidate the underlying mechanisms. The BCG vaccine’s potential as an immunological adjuvant and its role in preventing and treating non-targeted infections and diseases warrant careful consideration in vaccination strategies.
doi.org/10.1097/CM9.0000000000002890
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